B cell malignancies or neoplasms may arise in all lymphoid tissues where B cells are normally being produced. Most patients with B cell neoplasms are initially diagnosed with disease involving bone marrow or lymph nodes. In the case of bone marrow involvement, the transformed B cells frequently circulate through the blood and become widely disseminated throughout peripheral lymphoid tissues. However, B cell malignancies may also arise in some nonlymphoid tissues such as the thyroid, gastrointestinal tract, salivary glands and conjunctiva.
Well known B-cell-derived malignancies include B-cell chronic lymphocytic leukemia, mantle cell lymphoma, Burkitt lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, multiple myeloma, Hodgkin's lymphoma, hairy cell leukemia, primary effusion lymphoma and AIDS-related NHL. B-cell malignancies comprise more than 85% of diagnosed lymphomas.
CD32b is an example of an antigen expressed on such malignant cells, and recent studies have identified CD32b as a potential immunotherapeutic target for B-cell malignancies (Rankin et al. (2006) Blood 108: 2384-2391). CD32b is an integral membrane glycoprotein and is the predominant Fc receptor (FcR) (Amigorena et al. (1992) Science 256:1808-1812; Takai (2002) Nat. Rev. Immunol 2:580-592. The CD32b gene is expressed on B lymphocytes and its extracellular domain is 96% identical to CD32a (also known as FcγRIIA). CD32a is highly expressed by myeloid cells and is absent in B cells (Takai (2002) Nat. Rev. Immunol 2:580-592; Ravetch et al. (2001) Annu. Rev. Immunol. 19:275-290), and they bind IgG complexes in an indistinguishable manner but create two functionally heterogeneous responses to receptor ligation. The fundamental difference is that the A isoform initiates intracellular signaling leading to cell activation such as phagocytosis and respiratory burst, whereas the B isoform initiates inhibitory signals, e.g. inhibiting B-cell activation. CD32b is expressed in two isoforms (CD32b1 and CD32b2) that share the same extracellular and transmembrane domains but differ slightly in the intracellular domain. CD32b1 has an insertion in the intracellular part that prevents internalization of the receptor. The CD32b1 isoform is expressed preferentially on B cells whereas myeloid cells preferentially express the CD32b2 isoform (Daeron (1997), Ann Rev Imm: 203-234).
Accordingly, the identification and generation of monoclonal antibodies specific for human CD32b is essential for novel treatments based on therapeutic antibodies, including monoclonal antibody treatment of B-cell lymphoproliferative disorders. Such identification and generation has been hindered by the homology of CD32A to CD32b within the extracellular region (Brooks et al. (1989) J. Exp. Med. 170:1369-1385).
Anti-CD32b monoclonal antibodies with apparently no or very little interaction with CD32a have been reported (WO2006/066078), but need remains for new, effective anti-CD32b monoclonal antibodies for use in therapy, in particular for use in cancer therapy. In this context at least the following four areas of therapeutic application of monoclonal antibodies are anticipated: (1) the use of monoclonal antibodies as single agents in cancer therapy; (2) the use of monoclonal antibodies in combination with other therapy, such as chemotherapy to enhance antitumor responses; (3) the use of agents coupled to monoclonal antibodies as radioimmunoconjugates and immunotoxins; (4) the use of monoclonal anti-CD32b antibodies as an adjuvants, i.e. by boosting an immune response through blocking of the inhibitory effects of CD32b.